We demonstrated that in patients diagnosed with COVID-19, D-dimer elevation upon admission was common and was associated with both increased disease severity and in-hospital mortality. D-dimers are one of the fragments produced when plasmin cleaves fibrin to break down clots. The assays are routinely used as part of a diagnostic algorithm to exclude the diagnosis of thrombosis. However, any pathologic or non-pathologic process that increases fibrin production or breakdown also increases plasma D-dimer levels . Examples include deep vein thrombosis/pulmonary embolism, arterial thrombosis, disseminated intravascular coagulation, and conditions such as pregnancy, inflammation, cancer, chronic liver diseases, post trauma and surgery status, and vasculitis. Among adults admitted to the emergency room, infections, instead of VTE/PE, are the most common reason for D-dimer elevation . In the present study, no patient had confirmed PE/DVT, which supports the application of D-dimer in COVID-19 not just as a diagnostic tool for thromboembolism. In addition, only three patients in the elevated D-dimer group (3/185, 1.6%) with D-dimer levels of 42.8 mg/L, 89.0 mg/L, and 71.0 mg/L had ISTH-DIC scores of ≥ 5, which is laboratory evidence compatible with overt DIC. Thus, the majority of the included patients with D-dimer elevation in our study did not have overt DIC. Due to the retrospective nature of the study and small number of patients with ISTH-DIC score consistent with overt DIC, it is difficult to tell from our data if D-dimer elevation is related with DIC.
Several studies have shown that D-dimer levels are associated with severity of community-acquired pneumonia and clinical outcome [7, 15]. However, D-dimer has not been used as a biomarker for viral pneumonia [16, 17]. Though D-dimer elevation has been observed in articles describing the clinical features of COVID-19, whether the level of D-dimer is a marker of severity has not been examined.
In the present study, there is a significant correlation between D-dimer levels and disease severity stratified by the area of affected lungs on chest CT, oxygenation index, as well as clinical staging according to the interim guideline. In addition, a higher percentage of D-dimer elevation was seen in the present study than previously reported [2, 5]. This may be due to the higher percentage of severe/critically ill cases referred to our hospital, which is another demonstration of the correlation between D-dimer level and disease severity. This suggests that the assay may be used early as a marker of severity before chest CT scans or as a complement to CT and clinical staging.
In-hospital mortality was also associated with increased D-dimer levels, suggesting that the assay may be used as a single useful biomarker for clinical outcome in patients with COVID-19. Zhou et al. reported that D-dimer > 1 μg/ml is a risk for mortality . The study objective, design, population, and statistical analysis of Zhou’s study and those of ours are different. Zhou’s study was a retrospective cohort study to describe risk factors for mortality and clinical course, which included patients who had been discharged or had died by January 31, 2020. The mortality rate was higher compared to that in our study (28.3% vs. 6.9%). To explore risk factor for mortality, Zhou et al. chose age, coronary heart disease, SOFA score, lymphocyte, and D-dimer as variables for multivariable logistic regression model. D-dimer was defined as a categorical variable in the analysis, and levels of ≤ 0.5 μg/L, > 0.5 to ≤ 1 μg/L, and > 1 μg/L were chosen. The laboratory method for D-dimer assay was not described. In the present case control study, we focused on the predictive value of D-dimer for in-hospital deaths using receiver operating characteristic analysis. In the analysis, D-dimer is defined as a continuous variable. Testing used immunoturbidimetric assay with reference range of 0–0.50 mg/L (Sysmex, CS5100). Despite the differences in study design and analysis, the findings and conclusions of the two studies are not inconsistent. Zhou et al. concluded that the potential risk factors of older age, high SOFA score, and D-dimer greater than 1 μg/L (instead of levels of ≤ 0.5 μg/L, or > 0.5 to ≤ 1 μg/L) could help clinicians to identify patients with poor prognosis. We found that when using the cutoff value of 2.14, D-dimer levels upon admission for in-hospital mortality has an AUC of 0.846. The sensitivity and specificity are 88.2% and 71.3%, respectively. The findings of this present study suggest that an elevated D-dimer level on admission (> 2.14 mg/L) may identify patients at higher risk for in-hospital mortality and therefore inform physicians about suitable candidates for intensive care and early intervention.
It is worth noting that the findings suggest associations between D-dimer levels and disease severity and mortality only. Evidence is still lacking as to the causal mechanisms and whether the associations are specific effects of SARS-CoV-2 infection or are consequences of systemic inflammatory response. In SARS-COV-2 infection, dysregulation of coagulation/anti-coagulation cascades results in worsening lung pathology . In influenza, the pathogenesis by augmenting viral replication and immune pathogenesis can be attributed to an aberrant coagulation system, including both the cellular and protein components . The pathological features of COVID-19 include diffuse alveolar damage with cellular fibromyxoid exudates, desquamation of pneumocytes and hyaline membrane formation, pulmonary edema with hyaline membrane formation, and interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, which greatly resemble those seen in SARS and MERS coronavirus infection [20, 21]. Presumably, the observed D-dimer elevation signify a hyperfibrinolysis state and increased inflammatory burden induced in SARS-COV-2 infection. In our logistic regression model to estimate risk factors associated with mortality, systematic anticoagulation therapy was not significantly associated with reduced risk of mortality. However, in a recent observational study including 2773 hospitalized COVID-19 patients, Paranjpe et al. found that treatment dose anticoagulant was associated with a reduced risk of mortality, especially among patients who required mechanical ventilation . And longer duration of treatment was associated with a reduced risk of mortality (adjusted HR of 0.86 per day, 95% CI 0.82–0.89, p < 0.001). Whether anticoagulation therapy confers a survival benefit in patients hospitalized for COVID-19 needs further research with prospective randomized trials. Currently, the potential benefits need to be weighed against risk of bleeding.
This study has some limitations. First, the current study was done in a single center. The overall mortality (6.9%) was lower compared with that reported in other studies done in Wuhan [2, 6] and considerably higher than those reported by other provinces [5, 23]. Further researches may be needed when extrapolated to wider patient population. Second, the study is retrospective in nature. The patients included were not systematically assessed for the presence of PE/DVT but only when clinically suspected. Third, we did not look into the value of serial D-dimer monitoring in assessing COVID-19 patients.